Administration regime for nitrocatechols

ABSTRACT

A compound of formula (I) 
                         
where R 1 , R 2 , X, Y, n, m, R 3 , R 4 , R 5 , R 6  and R 7  are as defined herein, for use in the prophylaxis or treatment of a central and peripheral nervous system disorder, wherein the compound of formula (I) is administered prior to sleep, before bedtime or at bedtime.

This application is a continuation of U.S. application Ser. No.13/583,375, filed Sep. 7, 2012, which, in turn, is a 35 U.S.C. § 371national stage filing of International Application No.PCT/GB2011/052056, filed Oct. 21, 2011, which, in turn, claims priorityto U.S. Provisional Application No. 61/441,988, filed Feb. 11, 2011. Theentire contents of each of the aforementioned applications areincorporated herein by reference.

This invention relates to the use of substituted nitrocatechols offormula (I) in the treatment of central and peripheral nervous systemdisorders according to a specified administration (dosing) regimen(regime).

The rationale for the use of COMT inhibitors as adjuncts tolevodopa/aromatic L-amino acid decarboxylase inhibitor (AADCi) therapyis based on their ability to reduce metabolic O-methylation of levodopato 3-O-methyl-levodopa (3-OMD). The duration of levodopa-inducedclinical improvement is brief as a result of the short in vivo half-lifeof levodopa which contrasts with the long half-life of 3-OMD.Additionally, 3-OMD competes with levodopa for transport across theblood-brain barrier (BBB), which means that only a very limited amountof an orally administered dose of levodopa actually reaches the site ofaction, i.e. the brain. Commonly, within only a few years of startinglevodopa therapy with the usual administration regime, levodopa-inducedclinical improvement declines at the end of each dose cycle, giving riseto the so-called ‘wearing-off’ pattern of motor fluctuations. A closerelationship between the ‘wearing-off’ phenomenon and accumulation of3-OMD has been described (Tohgi, H., et al., Neurosci. Letters,132:19-22, 1992). It has been speculated that this may result fromimpaired brain penetration of levodopa due to competition for thetransport system across the BBB with 3-OMD (Reches, A. et al.,Neurology, 32:887-888, 1982) or more simply that there is less levodopaavailable to reach the brain (Nutt, J. G., Fellman, J. H., Clin.Neuropharmacol., 7:35-49, 1984). In effect, COMT inhibition protectslevodopa from O-methylation metabolic breakdown in the periphery, andparticularly in the intestine, such that with repeated doses oflevodopa, the mean plasma levodopa concentration is raised. In additionto reduced competition for transport into the brain, a significantlygreater percentage of the orally administered dose of levodopa is ableto reach the site of action. Thus COMT inhibition serves to increase thebioavailability of levodopa and the duration of antiparkinsonian actionis prolonged with single administrations of levodopa (Nutt, J. G.,Lancet, 351:1221-1222, 1998).

The most potent COMT inhibitors reported thus far are3,4-dihydroxy-4′-methyl-5-nitrobenzophenone (Tolcapone, Australian pat.AU-B-69764/87) and(E)-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide(Entacapone, German pat. DE 3740383 A1).

Although sharing essentially the same pharmacophore, tolcapone differsfrom entacapone in that it easily enters the central nervous systems(CNS) and is able to inhibit cerebral COMT as well as peripheral COMT.Shortly after its launch, tolcapone was withdrawn from the market afterseveral cases of hepatotoxicity were reported including threeunfortunate deaths from fatal fulminant hepatitis. Today tolcapone canonly be used in Parkinsonian patients who are unresponsive to othertreatments and only with regular monitoring of liver function, which isexpensive and inconvenient for the patient. Although the actualmechanistic causes of the liver toxicity associated with tolcapone arenot fully understood, in vitro studies have shown that tolcapone may bereduced metabolically to reactive intermediates and it has beenspeculated that these may form covalent adducts with hepatic proteinsresulting in hepatocellular injury (Smith, K. S. et al, Chem. Res.Toxicol., 16:123-128, 2003).

Entacapone on the other hand, although sharing the same nitrocatecholpharmacophore with tolcapone, is not associated with liver toxicity andis generally regarded as a safe drug. Unfortunately, however, entacaponeis a significantly less potent COMT inhibitor than tolcapone and has amuch shorter in-vivo half-life. This means that entacapone has a verylimited duration of effect and as a consequence, the drug must beadministered in very high doses with every dose of levodopa taken by thepatient. As such, the clinical efficacy of entacapone has beenquestioned—indeed a recent study (Parashos, S. A. et al., Clin.Neuropharmacol., 27(3): 119-123, 2004) revealed that the principalreason for discontinuation of entacapone treatment in Parkinson'sdisease patients was a perceived lack of efficacy.

Furthermore, the relatively short in-vivo half-life of known COMTinhibitors requires continuous treatment regimens normally involving theadministration of several doses a day which many patients find to beburdensome. For example, tolcapone has to be administered three times aday. This factor can therefore interfere with patient compliance andquality of life.

Accordingly, there is still a need for COMT inhibitors exhibitingbalanced properties of bioactivity, bioavailability and safety. Inparticular, there is a need for COMT inhibitors having a long in-vivohalf-life and, thus, a prolonged action on COMT enabling fewer dosagesto obtain the desired therapeutic effect.

The applicant has previously discovered compounds which, despite havinga relatively short half life, are very potent COMT inhibitors endowedwith exceptionally long duration of action compared to COMT inhibitorsin the prior art (see WO2007/013830).

These compounds, which are shown hereinbelow as compounds of generalformula (I), also markedly enhance the bioavailability of levodopa andincrease the delivery of levodopa to the brain. The compoundssignificantly augment the levels of dopamine in the brain over a longperiod of time.

Even more surprisingly, the increased levels of levodopa are maintainedsteady over extended periods of time. These sustained effects upon bothCOMT activity and levodopa bioavailability after the administration ofcompounds of general formula (I) are markedly greater than thoseobserved with tolcapone, the only COMT inhibitor thus far known to beendowed with a reasonably long duration of action. (Tolcapone has aterminal half life of around 2 hours and must be administered around 3times per day.) Furthermore, compounds of general formula (I) produce asteady increase in levodopa delivery to the brain over extended periodsof time, which contrasts with that observed with tolcapone, which isprone to induce marked oscillations in the brain delivery of levodopa.Thus compounds of general formula (I) are more likely to be endowed withtherapeutic advantages due to sustained constant elevation of levodopalevels whilst the use of tolcapone is likely to induce undesirableside-effects such as dyskinesia due to abrupt increases and decreases inlevodopa levels.

The present invention is based on a surprisingly advantageousadministration regimen for the administration of the compounds offormula (I) which maximises the COMT inhibitory effect of the compounds.

Accordingly, in a first aspect the present invention relates to acompound of formula (I)

where R₁ and R₂ are the same or different and signify hydrogens, groupshydrolysable under physiological conditions, or optionally substitutedalkanoyls or aroyls; X signifies a methylene group; Y represents O, S orNH; n represents 0, 1, 2 or 3; m represents 0 or 1; R₃ signifies apyridine N-oxide group according to the formula A, B, or C, which isconnected as indicated by the unmarked bond:

where R₄, R₅, R₆ and R₇ are the same or different, and signify hydrogen,alkyl, thioalkyl, alkoxy, aryloxy, thioaryl, alkanoyl, aroyl, aryl,amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino,alkylsulphonyl, arylsulphonyl, halogen, haloalkyl, trifluoromethyl,cyano, nitro or heteroaryl; or two or more of R₄, R₅, R₆ and R₇ takentogether signify aliphatic or heteroaliphatic rings or aromatic orheteroaromatic rings; the term ‘alkyl’, including its variant ‘alk-’ interms such as ‘alkoxy’, ‘alkanoyl’ mean carbon residues, straight orbranched, containing from one to six carbon atoms; the term ‘aryl’ meansa phenyl or naphthyl group; the term ‘heterocycloalkyl’ represents afour to eight-membered cyclic ring optionally incorporating at least oneatom of oxygen, sulphur or nitrogen; the term ‘heteroaryl’ represents afive or six-membered ring incorporating at least one atom of sulphur,oxygen or nitrogen; the term ‘halogen’ represents fluorine, chlorine,bromine or iodine; and if R₄, R₅, R₆ and R₇ represent alkyl or aryl theyare optionally substituted by one or more hydroxy, alkoxy or halogengroups; or a pharmaceutically acceptable salt, ester, carbamate orphosphate thereof;

for use in the prophylaxis or treatment of a central and peripheralnervous system disorder, wherein the compound of formula (I) isadministered prior to sleep, before bedtime or at bedtime.

In a second aspect the present invention relates to a compound offormula (I)

where R₁ and R₂ are the same or different and signify hydrogens, groupshydrolysable under physiological conditions, or optionally substitutedalkanoyls or aroyls; X signifies a methylene group; Y represents O, S orNH; n represents 0, 1, 2 or 3; m represents 0 or 1; R₃ signifies apyridine N-oxide group according to the formula A, B, or C, which isconnected as indicated by the unmarked bond:

where R₄, R₅, R₆ and R₇ are the same or different, and signify hydrogen,alkyl, thioalkyl, alkoxy, aryloxy, thioaryl, alkanoyl, aroyl, aryl,amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino,alkylsulphonyl, arylsulphonyl, halogen, haloalkyl, trifluoromethyl,cyano, nitro or heteroaryl; or two or more of R₄, R₅, R₆ and R₇ takentogether signify aliphatic or heteroaliphatic rings or aromatic orheteroaromatic rings; the term ‘alkyl’, including its variant ‘alk-’ interms such as ‘alkoxy’, ‘alkanoyl’ mean carbon residues, straight orbranched, containing from one to six carbon atoms; the term ‘aryl’ meansa phenyl or naphthyl group; the term ‘heterocycloalkyl’ represents afour to eight-membered cyclic ring optionally incorporating at least oneatom of oxygen, sulphur or nitrogen; the term ‘heteroaryl’ represents afive or six-membered ring incorporating at least one atom of sulphur,oxygen or nitrogen; the term ‘halogen’ represents fluorine, chlorine,bromine or iodine; and if R₄, R₅, R₆ and R₇ represent alkyl or aryl theyare optionally substituted by one or more hydroxy, alkoxy or halogengroups; or a pharmaceutically acceptable salt ester, carbamate orphosphate thereof;

for use in the prophylaxis or treatment of a central and peripheralnervous system disorder, wherein the compound of formula (I) isadministered without food and/or between intakes of food.

In a third aspect, the invention provides the use of a compound offormula (I) for the manufacture of a medicament for use in theprophylaxis or treatment of a central and peripheral nervous systemdisorder, wherein said compound is administered without food, betweenintakes of food, prior to sleep, before bedtime and/or at bedtime.

In a fourth aspect, the invention provide a method of prophylaxis ortreatment of a central and peripheral nervous system disorder,comprising administering to a patient suffering from said disorder,without food, between intakes of food, prior to sleep, before bedtimeand/or at bedtime a therapeutically effective amount of a compound offormula (I).

Surprisingly, the applicant has found that the compounds of formula (I)are advantageously administered to a patient who has a digestive systemwhich is as free from food as possible. Therefore, the compounds offormula (I) should preferably be administered to a patient without foodand/or between intakes of food e.g. between meals, prior to sleep,before bedtime or at bedtime. Administering the compound in this mannerresults in the compounds of formula (I) having better activity e.g. morelong lasting and increased inhibition of COMT.

Further, as mentioned, the COMT inhibitors of formula (I) are used as anadjunct to catecholamine therapy, so that the metabolism of thecatecholamine drug by COMT is decreased. The applicant has alsosurprisingly found that when a compound of formula (I) is administeredto a patient already taking a catecholamine, such as levodopa (L-DOPA),the effects of the compound of formula (I) are improved if the compoundof formula (I) is administered sequentially with the catecholamine. Inparticular, it has surprisingly been discovered that the compound offormula (I) adversely affects the bioavailability of levadopa, andlevadopa adversely affects the bioavailability of the compound offormula (I). Consequently, according to the invention the compound offormula (I) is administered prior to sleep, before bedtime or atbedtime, before or after the last daily dose of levodopa has been givento the patient and before the following day's dosage of levodopa isadministered. Therefore, the compound of formula (I) and thecatecholamine drug are not within the patient's digestive system at thesame time and/or not being substantially absorbed at the same time.

For the purpose of the present invention, last daily dose, last dose ofthe day, last daily administration and last administration of the dayhave the same meaning and can be used interchangeably.

The present invention will now be described with reference to theaccompanying drawings.

FIG. 1 shows mean plasma concentration-time profile of5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol(COMPOUND A) following fasting and fed conditions.

FIG. 2 shows mean levodopa plasma concentration-time profiles followingsingle oral administration of Sinemet® (levodopa/carbidopa) 100/25 mgadministered alone, administered with 50 mg COMPOUND A separated 1 h andadministered concomitantly with 50 mg COMPOUND A.

FIG. 3 shows mean S-COMT activity (metanephrine formed, pmol/mgprotein/h) profiles from baseline (pre-dose) following single oraladministration of Sinemet® 100/25 administered alone, administered with50 mg COMPOUND A separated 1 h, administered concomitantly with 50 mgCOMPOUND A and when COMPOUND A was administered alone.

As mentioned, because the compounds of formula (I) are extremely potent,they can potentially be administered in a single daily administration.

The compounds of formula (I) are preferably administered prior to sleep,before bedtime or at bedtime. The term ‘prior to sleep’ means that thecompound of formula (I) is administered shortly before the patient goesto sleep, for example less than 90 minutes prior to sleep, particularlyless than one hour prior to sleep, less than 30 minutes prior to sleepor immediately prior to sleep.

The term before bedtime (i.e. before going to bed) means particularlyless than 90 minutes before going to bed, particularly less than 60minutes before going to bed or less than 30 minutes before going to bed.The term at bedtime means less than 5 minutes before bedtime, forexample on going to bed.

In other words, the compound of formula (I) is taken by the patientbefore the patient goes to bed (i.e. before bedtime or at bedtime), e.g.less than 90 minutes before bedtime, particularly less than 60 minutesbefore bedtime, less than 30 minutes before bedtime or less than 5minutes before bedtime.

As will be clear in the context of the invention, the term ‘prior tosleep’ or ‘before bedtime’ does not mean any time in the day prior tosleep or going to bed, and in particular does not include, for example,12 hours before sleep or going to bed. Rather this term means the drugis taken in the period close to the patient going to sleep and probablyas part of the patient's bedtime routine.

In one embodiment, the compound of formula (I) is administered incombination therapy with a catecholamine drug. Preferably thecatecholamine drug is levodopa.

As such, the administration regimen of the compound of formula (I) andthe catecholamine drug may differ: each may be administered at the sametime or at different times. It will therefore be appreciated that thecompounds of the combination may be administered sequentially (e.g.before or after) or concomitantly, either in the same pharmaceuticalformulation (i.e. together), or in different pharmaceutical formulations(i.e. separately). Simultaneously in the same formulation is as aunitary formulation whereas simultaneously in different pharmaceuticalformulations is non-unitary. The administration regime of each of thetwo or more compounds in a combination therapy may also differ withrespect to the route of administration.

The applicant has surprisingly discovered that the compounds of formula(I) and the catecholamine drug each adversely affect the bioavailabilityof the other.

In particular, the compounds of formula (I) are administered prior tosleep, before bedtime or at bedtime, before or after the lastadministration of the day of the catecholamine drug and before the firstadministration of the next day of the catecholamine drug. This thereforeavoids the adverse consequence each drug has on the bioavailability ofthe other. Preferably the COMT inhibitory activity of the compounds offormula I is active prior to administration of the catecholamine drug.

In one embodiment, the compound of formula (I) is administered from 30to 150 minutes before or after the last daily administration of thecatecholamine drug. For example the compound of formula (I) isadministered at least 30-50 minutes, preferably at least one hour,before or after the last daily administration of the catecholamine drug.

In another embodiment, the compound of formula (I) is administered atleast one hour before or after the last daily administration of thecatecholamine drug is administered, and preferably the compound offormula (I) is administered once daily at least one hour before or afterthe last daily administration of the catecholamine drug. In embodimentsof the invention there is a period of at least two, three, four, five orsix hours between the administration of the catecholamine and thecompounds of formula (I).

Preferably the subsequent administration of the catecholamine isadministered at least two, more preferably at least three, and mostpreferably at least six hours after administration of the compound offormula (I). Suitably, the subsequent administration of thecatecholamine is administered 12 hours or 23 hours after administrationof the compound of formula (I). Preferably, the subsequentadministration of the catecholamine drug is the first daily dose ofcatecholamine drug of the next day.

In addition, the administration regime according to the inventioninvolves administration of the compound of formula (I) when the patienthas a digestive system free from food. The applicant has discovered thatthe compounds of formula (I) have improved bioavailability whenadministered to a patient when the patient does not have food in theirdigestive system. In particular, the compound of formula (I) should beadministered to the patient prior to sleep, before bedtime or atbedtime, without food after the patient has had their final meal of theday.

The term “a digestive system free from food” means that the part of thedigestive system where most of the absorption of the compound of formula(I) occurs is free from food, e.g. stomach, small intestine (duodenum,jejunum, ileum).

In one embodiment of the invention the compound of formula (I) isadministered at least one hour after the most recent intake of food andat least one hour before the next intake of food.

In one embodiment of the invention the compound of formula (I) isadministered from 0.25 to 12 hours, preferably from 0.5 to 6 hours, morepreferably from 0.75 to 4 hours, after an intake of food. In oneembodiment of the invention the compound of formula (I) is administeredafter 0.25 to 10 hours overnight fasting.

In one embodiment of the invention, the compound of formula (I) isadministered from 0.25 to 2 hours, preferably from 0.5 to 1.5 hours,before an intake of food.

Preferably the compound of formula (I) is administered prior to sleep,and more preferably less than one hour prior to sleep.

Most preferably, in order to avoid the interaction between the compoundof formula (I) and the catecholamine drug, and also to administer thecompound of formula (I) when the patient has a digestive system free offood, the compound of formula (I) is administered once daily prior tosleep, before bedtime or at bedtime.

As used herein, the term ‘effective daily dose’ is the effective dailyamount of compound administered when administered according to thedosing periodicity.

In the present invention, effective daily doses of compounds of generalformula (I) are in the range of about 1 to about 1200 mg/day, preferablyabout 1 to about 900 mg/day, more preferably about 5 to about 400mg/day, even more preferably about 25 to about 300 mg/day, for examplespecific daily doses of 1 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30mg, 50 mg, 100 mg, 200 mg, 400 mg, 800 mg or 1200 mg.

As used herein, the term “dosage unit” refers to the amount of compoundadministered in each dosing periodicity.

It is preferred that individual dosage units of compounds of generalformula (I) are in the range of about 1 to about 2400 mg, morepreferably about 1 to about 1200 mg, even more preferably about 1 toabout 800 mg, for example 1 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg,30 mg, 50 mg, 100 mg, 200 mg, 400 mg, 800 mg or 1200 mg.

As mentioned above, COMT inhibitors are often used as adjuncts tocatecholamine compounds because they reduce their metabolicO-methylation. In particular, COMT inhibitors are often used as adjunctsto levodopa/aromatic L-amino acid decarboxylase inhibitor (AADCi)therapy because they reduce metabolic O-methylation of levodopa to3-O-methyl-levodopa (3-OMD).

Therefore, preferably, the pathological states treated by the compoundsare central and peripheral nervous system-associated disorders of humanswhich benefit from administration of a COMT inhibitor.

When the compound of formula (I) is administered in combination with acatecholamine drug, it is possible that the catecholamine drug isadministered sequentially or concomitantly with an AADCi, in particularcardidopa or benserazide.

The compounds of general formula (I), the catecholamine drug and theAADCi may be administered separately or in any combination. They may beadministered concomitantly (for example, simultaneously) orsequentially, and with the same or differing dosing periodicity. Forexample, the compounds of the general formula (I) can be concomitantlyor sequentially administered with the catecholamine drug.

The use of the compounds according to the invention is for thepropylaxis or treatment of central and peripheral nervous systemdisorders. The central and peripheral nervous system disorder is, forexample, a mood disorder, gastrointestinal disturbance, oedema formationstate, hypertension or a movement disorder. Preferably, the disordersare movement disorders including disorders involving parkinsonism,Parkinson's Disease, and restless leg syndrome. The most preferredcentral and peripheral nervous system disorder is Parkinson's Disease.

As used herein, the term treatment and variations such as ‘treat’ or‘treating’ refer to any regime that can benefit a human or non-humananimal. In addition the compounds of formula (I) can be used forprophylaxis (preventative treatment). Treatment may include curative,alleviation or reducing effects, such effects relating to one or more ofthe symptoms associated with the central and peripheral nervoussystem-associated disorders.

One particular embodiment of the invention that can be mentioned is acompound of formula (I), particularly5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-dioland its pharmacologically acceptable salts, esters, carbamates andphosphates, for use in combination with a catecholamine drug,particularly levodopa, for the prophylaxis or treatment of central andperipheral nervous system disorder, particularly a movement disordersuch as Parkinson's disease, wherein the compound of formula (I) isadministered orally once daily at least one hour before or after thelast daily dose of the catecholamine drug and prior to sleep, beforebedtime or at bedtime and/or without food and/or between intakes of foodand/or at least one hour after the most recent intake of food and atleast one hour before the next intake of food.

According to another aspect of the present invention there is provided amethod of treating at least one pathological state in a patient in needthereof comprising administering, without food and/or between intakes offood and/or prior to sleep and/or before bedtime and/or at bedtimeand/or before or after administration of a catecholamine drug, apharmacologically effective dose of a compound of general formula (I) asdefined above to the patient.

According to another aspect of the invention there is provided a methodfor inhibiting COMT in a subject, comprising administering, without foodand/or between intakes of food and/or prior to sleep and/or beforebedtime and/or at bedtime and/or before or after administration of acatecholamine drug, an effective dose of a compound of general formula(I) as defined above to the subject.

According to another aspect of the invention there is provided a methodfor increasing levels of levodopa in the brain of a subject beingtreated with levodopa, comprising administering, without food and/orbetween intakes of food and/or prior to sleep and/or before bedtimeand/or at bedtime and/or before or after administration of acatecholamine drug, an effective dose of a compound of general formula(I) as defined above to the subject.

According to another aspect of the invention there is provided a methodfor increasing levels of levodopa in the plasma of a subject beingtreated with levodopa, comprising administering, without food and/orbetween intakes of food and/or prior to sleep and/or before bedtimeand/or at bedtime and/or before or after administration of acatecholamine drug, an effective dose of a compound of general formula(I) as defined above to the subject.

According to another aspect of the invention there is provided a methodfor decreasing levels of 3-O-methyl-levodopa (3-OMD) in the brain of asubject being treated with levodopa, comprising administering, withoutfood and/or between intakes of food and/or prior to sleep and/or beforebedtime and/or at bedtime and/or before or after administration of acatecholamine drug, an effective dose of a compound of general formula(I) as defined above to the subject.

According to another aspect of the invention there is provided a methodfor decreasing levels of 3-OMD in the plasma of a subject being treatedwith levodopa, comprising administering, without food and/or betweenintakes of food and/or prior to sleep and/or before bedtime and/or atbedtime and/or before or after administration of a catecholamine drug,an effective dose of a compound of general formula (I) as defined aboveto the subject.

According to another aspect of the invention there is provided a methodfor increasing bioavailability of levodopa in the brain of a subjectbeing treated with levodopa, comprising administering, without foodand/or between intakes of food and/or prior to sleep and/or beforebedtime and/or at bedtime and/or before or after administration of acatecholamine drug, an effective dose of a compound of general formula(I) as defined above to the subject.

According to another aspect of the invention there is provided a methodfor increasing bioavailability of levodopa in the plasma of a subjectbeing treated with levodopa, comprising administering, without foodand/or between intakes of food and/or prior to sleep and/or beforebedtime and/or at bedtime and/or before or after administration of acatecholamine drug, an effective dose of a compound of general formula(I) as defined above to the subject.

The present invention also relates to a package comprising apharmaceutical composition of a compound of the general formula (I) incombination with instructions to administer said formulation withoutfood and/or between intakes of food and/or prior to sleep and/or beforebedtime and/or at bedtime and/or before or after administration of acatecholamine drug.

For the compounds of formula (I), the following definitions arepreferred.

Groups hydrolysable under physiological conditions represent groupscleavable in vivo, at physiological conditions of pH and temperature. Onpage 1354 of the 6^(th) edition of “Foye's Principles of MedicinalChemistry”, 2006, eds. Wolter Kluwer, the pH values for tissue fluidsare indicated. Examples of groups hydrolysable under physiologicalconditions for the —OH functional group are esters, carbamates andphosphates. Further examples of groups hydrolysable under physiologicalconditions for the —OH functional group are well known to the skilled inthe art and can be found for example on pages 101-103 from Korolkovas inEssentials of Medicinal Chemistry, 2^(nd) edn., 1988, eds. John Wiley &Sons and on page 426 of Krogsgaard-larsen et al in Textbook of DrugDesign and Discovery, 3^(rd) edn., 2002, eds. Taylor & Francis.

Preferably, R₄, R₅, R₆ and R₇ independently from each other representhydrogen, C₁-C₆-alkyl, C₆-C₁₂ aryl, C₁-C₆-thioalkyl, C₁-C₆-alkoxy,C₆-C₁₀-aryloxy, C₆-C₁₀-thioaryl, C₁-C₆-alkanoyl, C₇-C₁₁-aroyl, amino,C₁-C₆-alkylamino, di-C₁-C₆-alkylamino, C₃-C₁₂-cycloalkylamino,C₄-C₈-heterocycloalkylamino, C₁-C₆-alkylsulphonyl, C₆-C₁₀-arylsulphonyl,halogen, C₁-C₆-haloalkyl, trifluoromethyl, cyano, nitro or heteroaryl.

When R₄, R₅, R₆ and/or R₇ represent C₁-C₆-alkyl residues, preferably R₄,R₅, R₆ and/or R₇ represent methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, tert-butyl, pentyl, or hexyl.

When R₄, R₅, R₆ and/or R₇ represent C₆-C₁₂-aryl residues, preferably R₄,R₅, R₆ and/or R₇ represent phenyl or naphthyl.

When R₄, R₅, R₆ and/or R₇ represent C₁-C₆-thioalkyl residues, preferablyR₄, R₅, R₆ and/or R₇ represent thiomethyl, thioethyl, thio-n-propyl,thio-isopropyl, thio-n-butyl, thio-n-pentyl, or thio-n-hexyl.

When R₄, R₅, R₆ and/or R₇ represent C₁-C₆-alkoxy residues, preferablyR₄, R₅, R₆ and/or R₇ represent methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, sec-butoxy or tert-butoxy.

When R₄, R₅, R₆ and/or R₇ represent C₆-C₁₀-aryloxy residues, preferablyR₄, R₅, R₆ and/or R₇ represent phenoxy or naphthoxy.

When R₄, R₅, R₆ and/or R₇ represent C₆-C₁₀-thioaryl residues, preferablyR₄, R₅, R₆ and/or R₇ represent thiophenyl or thionaphthyl.

When R₄, R₅, R₆ and/or R₇ represent C₁-C₆-alkanoyl residues, preferablyR₄, R₅, R₆ and/or R₇ represent methanoyl, ethanoyl, propanoyl orbutanoyl.

When R₄, R₅, R₆ and/or R₇ represent C₇-C₁₁-aroyl residues, preferablyR₄, R₅, R₆ and/or R₇ represent benzoyl or naphthoyl.

When R₄, R₅, R₆ and/or R₇ represent C₁-C₆-alkylamino residues,preferably R₄, R₅, R₆ and/or R₇ represent methylamino, ethylamino,n-propylamino, isopropylamino or n-butylamino.

When R₄, R₅, R₆ and/or R₇ represent di-C₁-C₆-alkylamino residues,preferably R₄, R₅, R₆ and/or R₇ represent dimethylamino, diethylamino,di-n-propylamino, di-n-butylamino, di-isopropylamino, methylethylamino,methylpropylamino or ethylpropylamino.

When R₄, R₅, R₆ and/or R₇ represent C₃-C₁₂-cycloalkylamino residues,preferably R₄, R₅, R₆ and/or R₇ represent pyrrolidino, piperidino,cyclohexylamino or dicyclohexylamino.

When R₄, R₅, R₆ and/or R₇ represent C₄-C₈-heterocycloalkylaminoresidues, preferably R₄, R₅, R₆ and/or R₇ represent morpholino,2,6-dimethylmorpholino, 3,5-dimethylmorpholino, piperazino,N-methylpiperazino or N-ethylpiperazino.

When R₄, R₅, R₆ and/or R₇ represent C₁-C₆-alkylsulphonyl orC₆-C₁₀-arylsulphonyl residues, preferably R₄, R₅, R₆ and/or R₇ representmethylsulfonyl, ethylsulfonyl, phenylsulfonyl, or tolylsulfonyl.

When R₄, R₅, R₆ and/or R₇ represent halogen residues, preferably R₄, R₅,R₆ and/or R₇ represent chloro, bromo, iodo or fluoro.

When R₄, R₅, R₆ and/or R₇ represent C₁-C₆-haloalkyl residues, preferablyR₄, R₅, R₆ and/or R₇ represent chloromethyl, fluoromethyl,dichloromethyl, difluoromethyl, trichloromethyl or trifluoromethyl.

When R₄, R₅, R₆ and/or R₇ represent heteroaryl residues, preferably R₄,R₅, R₆ and/or R₇ represent pyridyl, pyrimidyl, isoxazolyl, oxazolyl,isoxadiazolyl, oxadiazolyl, triazolyl or tetrazolyl.

When two or more of residues R₄, R₅, R₆ and R₇ taken together representaliphatic or heteroaliphatic rings or aromatic or heteroaromatic rings,the two or more residues preferably represent aliphatic orheteroaliphatic rings or aromatic or heteroaromatic rings. Preferredcombined residues are indolizinyl, isoindolyl, indolyl, indazolyl,purinyl, quinolizinyl, naphthyridinyl, isoquinolyl and quinolyl.

Where they represent aryl or alkyl, the above substituents R₄, R₅, R₆and R₇ may optionally be substituted one or more times by hydroxy,alkoxy or halogen groups.

In the present description of medical indications, treatments and dosingregimens for pharmaceutical compositions containing compounds accordingto general formula (I) of the invention, the most preferred example of acompound according to the general formula (I) is5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol,henceforth designated as compound A, and its pharmacologicallyacceptable salts, esters, carbamates and phosphates. The half life ofcompound A is relatively short given its long duration of action.

Other preferred compounds of the above general formula (I) for use inthe subsequent medical indications, treatments and dosing regimensinclude3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-4-(trifluoromethyl)pyridine-1-oxide,2-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-4,6-dimethylpyridine-1-oxide,3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2-methyl-6-(trifluoromethyl)pyridine-1-oxide,5-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2-(trifluoromethyl)pyridine-1-oxide,5-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2-methyl-4-(trifluoromethyl)pyridine-1-oxide,3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine-1-oxide,3,5-dichloro-4-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)pyridine-1-oxide,3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine-1-oxide,2-bromo-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-4,5,6-trimethylpyridine-1-oxide,2-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-4,5,6-trimethylpyridine-1-oxide,3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2-(trifluoromethyl)pyridine-1-oxide,2,5-dichloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-4,6-dimethylpyridine-1-oxide,3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)pyridine-1-oxide,3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2-fluoropyridine-1-oxide,4-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2-fluoropyridine-1-oxide,2-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-6-fluoropyridine-1-oxide,2-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-6-methylpyridine1-oxide,2-bromo-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-6-methylpyridine-1-oxide,and2-bromo-5-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-4,6-dimethylpyridine-1-oxideand their pharmacologically acceptable salts, esters, carbamates orphosphates.

Details of the preparation of compounds of general formula (I) can befound in WO2007/013830A1.

The compounds of general formula (I) may also be present in the form ofpharmacologically acceptable salts, esters, carbamates or phosphatesthereof. Suitable pharmaceutically acceptable counter ions are known tothe art.

It is also possible to use prodrugs of compounds of the general formula(I) in order to alter the therapeutic profile of the active compound.

The compound of formula (I) is administered as a pharmaceuticalcomposition. For the preparation of pharmaceutical compositions ofcompounds of general formula I, inert pharmaceutically acceptablecarriers are admixed with the active compounds. The pharmaceuticallyacceptable carriers may be solid or liquid. Solid form preparationsinclude powders, tablets, dispersible granules and capsules. A solidcarrier can be one or more substances which may also act as diluent,flavouring agent, solubiliser, lubricant, suspending agent, binder,glidant, or disintegrant; it may also be an encapsulating material.

Preferably the pharmaceutical composition is in unit dosage form, e.g. apackaged preparation, the package containing discrete quantities of thepreparation, for example packaged tablets, capsules and powders in vialsor ampoules.

In general, the compound of formula (I) is administered orally.

The compound of formula (I) typically is administered from once a day toabout once weekly.

For the avoidance of doubt, whenever the compound of formula (I) isadministered with a periodicity lower than once a day (e.g. onceweekly), it is understood that it will be administered prior to sleep,before bedtime or at bedtime, before or after the last daily dose oflevodopa of the day(s) of the week where compound (I) should beadministered and not every day, as levodopa. For example, for a onceweekly administration regime, if compound (I) is administered on thefirst day of week one, it will be administered prior to sleep, beforebedtime or at bedtime, before or after the last daily dose of levodopaof that day. The next administration will occur on the first day of weektwo, prior to sleep, before bedtime or at bedtime, before or after thelast daily dose of levodopa of that day and so on. Throughout thisperiod levodopa is administered every day (in several doses).

According to the methods described above, the compound of formula (I) istypically administered from once a day to about once weekly.

Other aspects of the invention are as defined in the claims.

EXAMPLES Example 1 Preparation of Compound A(5-[3-(2,5-Dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol)

-   a) To a stirred solution of 3,4-dibenzyloxy-5-nitrobenzoic acid    (0.50 g, 1.319 mmol) in dimethylformamide (5 mL) at room temperature    was added 1,1-carbonyldiimidazole (0.24 g, 1.45 mmol) in one    portion. After stirring for ninety minutes,    2,5-dichloro-N′-hydroxy-4,6-dimethylnicotinamide (0.40 g, 1.45 mmol)    was added in one portion. The resulting mixture was stirred at    135° C. for five hours and then at room temperature overnight. The    reaction mixture was poured onto ice-2 N HCl (100 mL) and the    resulting precipitate was filtered off, washed with water and dried    in air. Recrystallisation from isopropanol gave a pale yellow solid    (0.55 g, 72%).-   b) To a stirred solution of the solid obtained above (0.50 g, 0.866    mmol) in dichloromethane (20 mL) was added urea-hydrogen peroxide    addition complex (0.41 g, 4.33 mmol) in one portion. The mixture was    cooled in an ice-water bath and trifluoroacetic anhydride (0.73 g,    3.46 mmol) was added dropwise. The reaction mixture was allowed to    stir at room temperature overnight whereupon insoluble material was    filtered off. The filtrate was washed with water and brine, dried    over anhydrous magnesium sulphate, filtered and evaporated. The    residue was crystallised from isopropanol to give a pale yellow    solid (0.35 g, 68%).-   c) To a stirred solution of the solid obtained above (0.30 g, 0.5    mmol) in dichloromethane (10 mL) at −78° C. under argon was added    boron tribromide (0.38 g, 1.5 mmol) dropwise. The resulting purple    suspension was allowed to stir at room temperature for one hour,    then cooled again to −78° C. and carefully quenched by the addition    of water. After stirring at room temperature for one hour, the    precipitate was filtered off, washed with water and dried at 50° C.    under vacuum to afford the desired compound as yellow crystals (0.18    g, 87%) of m.p. 237-240° C.

Example 2 Pharmaceutical Formulation

Pharmaceutical formulations are prepared as follows:

Capsule:

Compound A 15.0% Lactose monohydrate 43.0% Microcrystalline cellulose30.0% Povidone 4.0% Croscarmellose sodium 5.0% Talc 2.0% Magnesiumstearate 1.0%Capsule:

Compound A 15.0% Microcrystalline cellulose 72.5% Ethylcellulose 5.0%Sodium starch glycolate 6.0% Colloidal Silicon Dioxide 0.5% Magnesiumstearate 1.0%Tablet:

Compound A 20.0% Microcrystalline cellulose 25.0% Calcium Phosphate,dibasic dihydrate 40.0% Povidone 6.0% Croscarmellose sodium 6.0% Talc2.0% Magnesium stearate 1.0%

Example 3 Dosing Regimen Example 3a Effect of Food

This study was an open-label, randomized, single administration,2-period, 2-sequence, crossover study in 12 healthy male subjects aimedto assess the effects of food on the pharmacokinetic (PK) profile ofCOMPOUND A and its metabolites. A single 50 mg dose of COMPOUND A (2×25mg capsules) was administered under fasted and fed conditions.

Blood samples were collected prior to and 0.5, 1, 1.5, 2, 3, 4, 6, 8,10, 12, 16 and 24 hours after administration of COMPOUND A.

Pharmacokinetic Results:

Following an oral single dose of 50 mg (2×25 mg capsules), thebioavailability of COMPOUND A was not equivalent under fasting and fedconditions, indicating the presence of a food effect on COMPOUND Apharmacokinetics (FIG. 1).

The COMPOUND A pharmacokinetic parameters following fasting and fedconditions are presented in Table 1. Summary of PK main results ofCOMPOUND A following fasting and fed conditions.

TABLE 1 Summary of PK main results of COMPOUND A following fasting andfed conditions. Fed Fasted C.V. C.V. F PARAMETER MEAN (%) MEAN (%)(treatment) p * C_(max) (ng/mL) 238.2 70.7 635.0 39.5 24.84 <0.01 ln(C_(max)) 5.2927 11.4 6.3868 5.9 41.50 <0.001 T_(max) (hours) ^(§) 4.0066.3 1.50 62.9 18 <0.05 AUC_(T) (ng · h/mL) 879.2 32.6 1989.5 49.5 15.95<0.01 ln (AUC_(T)) 6.7286 5.1 7.4900 6.4 34.22 <0.001 AUC_(∞) (ng ·h/mL) 1027.2 53.1 2113.6 43.3 36.53 <0.001 ln (AUC_(∞)) 6.8416 6.27.5771 5.5 52.24 <0.001 AUC_(T/∞) (%) 90.06 12.1 93.49 17.0 0.75 N.S.K_(el) (hours⁻¹) 0.4021 46.0 0.7581 38.9 15.99 <0.01 T_(1/2el) (hours)3.35 141.2 1.19 80.5 2.19 N.S. * N.S. = Not Significant. Significantwhenever p-value < 0.05; ^(§) For T_(max), the median is presented andthe statistical analysis is based on a non-parametric approach.C.V.—Coefficient of Variation

The ingestion of food decreased and delayed the absorption of COMPOUNDA; the administration of COMPOUND A immediately following consumption ofa high-fat, high-calorie meal significantly decreased the rate andextent of absorption compared to drug administration under fastingconditions. C_(max) and AUC parameters were significantly lower in thefed state compared to the fasted state (fed:fasted ratios of 31.73% forC_(max), 47.11% for AUC_(T) and 49.43% for AUC_(∞)). The T_(max) wassignificantly increased by the presence of food (4.00 hours in the fedstate versus 1.50 hours in the fasted state).

Conclusions:

The results show that the administration of COMPOUND A following foodintake results in a reduction in its bioavailability. The presence offood decreased the rate and extent of absorption of COMPOUND A, withdelayed peak plasma levels as compared to drug administration underfasting conditions.

Example 3b Administration of Levodopa and Compound a Concomitantly andSeparated by 1 Hour

This study was a single-centre, open-label, randomized, gender-balanced,crossover study with four consecutive single-administration treatmentperiods to assess the PK-PD interaction when standard release 25/100 mgcarbidopa/levodopa is administered concomitantly with a 50 mg COMPOUND Adose or 1 hour thereafter. Eighteen (18) subjects completed 2 treatmentperiods, 17 subjects completed 3 treatment periods and 16 subjectscompleted all 4 treatment periods. A total of 18 male [10 (55.6%)] andfemale [8 (44.4%)] subjects were enrolled in this study.

Treatment consisted of four single-administration periods.Single-administration of 50 mg COMPOUND A was constituted by 2 capsulesof 25 mg. Single-administration of immediate/standard release 25 mgcarbidopa/100 mg levodopa was constituted of 1 tablet of Sinemet®100/25. In accordance to the treatment sequence defined by therandomization, subjects were administered COMPOUND A and Sinemet® 100/25concomitantly in one period, Sinemet® 100/25 1 h after the COMPOUND Aadministration in another period, COMPOUND A alone in another period,and Sinemet® 100/25 alone in the remaining period. The washout periodbetween administrations was at least 3 weeks. In one treatment period,COMPOUND A and Sinemet® 100/25 were to be administered concomitantly; inanother treatment period, Sinemet® 100/25 was to be administered 1 hafter the COMPOUND A administration; in another treatment period,COMPOUND A was to be administered alone; in the remaining treatmentperiod, Sinemet® 100/25 was to be administered alone.

Mean levodopa C_(max) values were attained between 0.5 to 1.0 hourspost-administration. Thereafter, plasma levodopa concentrations declinedwith a mean elimination half-life (t1/2) ranging from 1.94 (Sinemet®100/25 alone) to 2.51 (Sinemet® 100/25 plus 50 mg COMPOUND Aconcomitantly) hours.

Following administration with COMPOUND A, the levodopa C_(max) increasedand the increase was higher when COMPOUND A was administeredconcomitantly, suggesting that a certain degree of interaction betweenCOMPOUND A and Sinemet® 100/25 may have occurred during the absorptionphase, leading to an increase in the rate of levodopa uptake and a lesssmooth increase in levodopa levels.

Mean levodopa plasma concentration-time profiles following single oraladministration of Sinemet® 100/25 administered alone, administered with50 mg COMPOUND A separated 1 h and administered concomitantly with 50 mgCOMPOUND A are illustrated in FIG. 2 (n=16 for concomitantadministration, n=17 for Sinemet® alone, n=18 for administrationseparated 1 h):

The Point Estimates and 90% Confidence Interval of the meanpharmacokinetic parameters of levodopa following 50 mg COMPOUND Aconcomitant administration (Test L1) and an administration separated 1 h(Test L2) with Sinemet® 100/25 are displayed in Table 2 (Sinemet® 100/25alone was taken as Reference):

TABLE 2 Point estimates and 90% CI of the mean pharmacokineticparameters of levodopa following 50 mg COMPOUND A concomitantadministration (Test L1) and an administration separated 1 h (Test L2)with Sinemet ® 100/25 C_(max) AUC_(0-t) AUC_(0-∞) Comparison PE (90% CI)PE (90% CI) PE (90% CI) Test L1/ 112.10 (96.94; 104.23 (96.88; 103.13(94.02; Reference L 129.64) 112.14) 113.12) Test L2/ 102.96 (89.36;114.56 (106.65; 109.85 (100.22; Reference L 118.62) 123.05) 120.41) TestL2/Test L1  91.84 (79.51; 109.91 (102.17; 108.51 (101.24; 106.09)118.24) 116.31) PE = Point estimate; CI = Confidence interval

A greater increase in the extent of exposure to levodopa (as assessed byAUC) occurred when Sinemet® 100/25 was administered 1 h after 50 mgCOMPOUND A.

The increase in levodopa AUC_(0-t) ranged from 4.23% when Sinemet®100/25 was administered concomitantly with 50 mg COMPOUND A(ratios=104.23 [96.88; 112.14]; means and 90% CIs) to 14.56% whenSinemet® 100/25 was administered 1 h after 50 mg COMPOUND A(ratios=114.56 [106.65; 123.05]). The increase in levodopa AUC_(0-∞)ranged from 3.13% when Sinemet® 100/25 was administered concomitantlywith 50 mg COMPOUND A (ratios=103.13 [94.02; 113.12]) to 9.85% whenSinemet® 100/25 was administered 1 h after 50 mg COMPOUND A(ratios=109.85 [100.22; 120.41]).

The increase in levodopa C_(max) ranged from 2.96% when Sinemet® 100/25was administered 1 h after 50 mg COMPOUND A (ratios=102.96 [89.36;118.62]) to 12.10% when Sinemet® 100/25 was administered concomitantlywith 50 mg COMPOUND A (ratios=112.10 [96.94; 129.64]), showing apreferred steadier increase in levodopa levels with administration ofSinemet® 100/25 was administered 1 h after COMPOUND A.

C_(max) of 3-OMD was lower when Sinemet® 100/25 was administered 1 hafter 50 mg COMPOUND A than when Sinemet® 100/25 was administeredconcomitantly with 50 mg COMPOUND A. A significant decrease in both rate(as assessed by C_(max)) and extent (as assessed by AUC) of systemicexposure to 3-OMD occurred when Sinemet® 100/25 was administeredconcomitantly and also 1 h after 50 mg COMPOUND A.

C_(max) and AUC of carbidopa were similar when Sinemet® 100/25 wasadministered alone and when administered with 50 mg COMPOUND A separated1 h. The increase in carbidopa C_(max) ranged from 5.33% when Sinemet®100/25 was administered 1 h after 50 mg COMPOUND A to 5.86% whenSinemet® 100/25 was administered concomitantly with 50 mg COMPOUND A.The increase in carbidopa AUC_(0-∞) ranged from 5.42% when Sinemet®100/25 was administered 1 h after 50 mg COMPOUND A to 9.20% whenSinemet® 100/25 was administered concomitantly with 50 mg COMPOUND A.

Mean COMPOUND A C_(max) values were attained between 2.5 to 4.0 hourspost-administration. Thereafter, plasma COMPOUND A concentrationsdeclined with a mean elimination half-life (t1/2) ranging from 1.14(COMPOUND A alone) to 1.28 (COMPOUND A with Sinemet® 100/25) hours.C_(max) of COMPOUND A was lower when COMPOUND A was administered 1 hbefore Sinemet® 100/25 than when was administered concomitantly withSinemet® 100/25 and even lower in relation to when COMPOUND A wasadministered alone. Following administration with Sinemet® 100/25, theCOMPOUND A C_(max) decreased and t_(max) increased, suggesting that acertain degree of interaction between COMPOUND A and Sinemet® 100/25 mayhave occurred during the absorption phase, leading to a delay in therate of COMPOUND A uptake. A statistical difference was found fort_(max) between 50 mg COMPOUND A administered concomitantly withSinemet® 100/25 and COMPOUND A administered alone (P=0.0020). Theincrease in COMPOUND A AUC_(0-∞) ranged from 4.18% when Sinemet® 100/25was administered concomitantly with 50 mg COMPOUND A to 4.74% whenSinemet® 100/25 was administered 1 h after 50 mg COMPOUND A. There was adecrease in COMPOUND A C_(max) of 9.21% when Sinemet® 100/25 wasadministered 1 h after 50 mg COMPOUND A.

Pharmacodynamic Results:

Mean S-COMT activity (metanephrine formed, pmol/mg protein/h) profilesfrom baseline (pre-administration) following single oral administrationof Sinemet® 100/25 administered alone, administered with 50 mg COMPOUNDA separated by 1 h, administered concomitantly with 50 mg COMPOUND A andwhen COMPOUND A was administered alone were as follows (FIG. 3) (n=16for concomitant administration, n=17 for Sinemet® alone, n=18 forCOMPOUND A alone and for administration separated by 1 h):

All COMPOUND A treatments significantly inhibited both peak and extentof S-COMT activity in relation to Sinemet® 100/25 alone administration.Following administration of COMPOUND A, maximum S-COMT inhibition(E_(max)) occurred between 3.42 h (COMPOUND A alone) and 4.58 h(Sinemet® 100/25 administered 1 h after 50 mg COMPOUND A)post-administration (tE_(max)), and ranged from 88.7% to 91.1%,respectively.

Conclusions:

The results were highly consistent across the multiple analysesperformed. All COMPOUND A treatments significantly inhibited both peakand extent of S-COMT activity in relation to Sinemet® 100/25 aloneadministration. The concomitant administration of COMPOUND A withSinemet® 100/25 showed an effect on both levodopa and COMPOUND Aabsorption. In the latter, as well as the slight C_(max) decrease, asignificant increase in COMPOUND A t_(max) was observed. With respect tolevodopa, delaying by 1 hour the administration with COMPOUND A, aC_(max) decrease (when compared to the increase observed with theconcomitant administration) was seen, suggesting that the possibleinteraction between COMPOUND A and Sinemet® 100/25 during the absorptionphase was reduced by separating both administrations. Furthermore,delaying by 1 hour the administration of levodopa with COMPOUND A, anincrease in levodopa systemic exposure (as assessed by AUC) wasobserved. This could be attributed to the absorption rate of COMPOUND Aand consequently to the inhibition of COMT. Indeed, and despite thesignificant increase in the t_(Emax) for both treatments with COMPOUND Aand Sinemet® 100/25 in relation to the administration of COMPOUND Aalone, the 1 hour separated administration induced a more sustainedabsorption rate of COMPOUND A in contrast to the abrupt and delayedabsorption observed with the concomitant administration. This may haveresulted in an early inhibition of COMT and consequent increase inlevodopa systemic exposure.

Example 3c Effect of Compound a on Patient's Levodopa Exposure afterAdministration of L-DOPA and COMPOUND a Concomitantly Followed byFurther Administration of L-DOPA 24 h Later

This study was a three-center, double-blind, randomised,placebo-controlled, cross-over study to investigate the tolerability andeffect a single administration of three dosages of COMPOUND A (25, 50and 100 mg) on the levodopa pharmacokinetics, motor response, anderythrocyte soluble catechol-O-methyltransferase activity in 10Parkinson's Disease patients concomitantly treated withlevodopa/dopa-decarboxylase inhibitor.

Subjects were eligible if they presented: a diagnosis of PD according tothe UK PDS Brain Bank diagnostic criteria; predictable signs ofend-of-dose deterioration despite “optimal” levodopa/AADCi therapy;being treated with a stable regimen of 3 to 8 doses of standard releaselevodopa/AADCi 100/25 mg per day within at least 1 week prior torandomization; modified Hoehn and Yahr stage of less than 5 in theoff-state; and/or mean duration of OFF stage≥1.5 h during waking hours.Concomitant anti-Parkinsonian medication (other than apomorphine,entacapone or tolcapone) was allowed in stable doses for at least 4weeks prior to randomization.

Manipulating the dose and frequency of levodopa administration is thecommon therapeutic approach to the onset of motor complications. This isusually described as optimization of levodopa therapy. “Optimal”levodopa/AADCi therapy is the levodopa/AADCi dosage and administrationregime, which produces the best motor response in a patient, i.e.absence or reduction to a minimum of end-of-dose deterioration(wearing-off) and/or motor complications.

The study consisted of four consecutive treatment periods, correspondingto the 4 different treatment options (Compound A 25 mg, 50 mg, 100 mg orplacebo). In each of the four treatment periods, subjects were to beadmitted to the study site 2 days prior to receiving the administrationof Compound A/Placebo (Day 1) and were to remain hospitalized(“in-patient”) until 48 h after receiving the administration of CompoundA/Placebo. The washout period between administrations was to be at least10 days. A follow-up visit was to occur approximately 2 weeks after thelast treatment administration or early discontinuation. During eachperiod, the COMPOUND A/Placebo capsules were to be co-administered withthe morning dose of levodopa/carbidopa 100/25 mg (1 tablet of Sinemet®25/100) or levodopa/benserazide 100/25 mg (1 tablet of Madopar®/Restex®125) on Day 3.

A total of 10 subjects were enrolled in this study: 10 subjectscompleted 3 treatment periods and 9 subjects completed all 4 treatmentperiods. The mean (±SD) age, height and weight were 58.40±10.24 (range:42-70) years, 1.69±0.14 (1.52-1.95) m, 71.5±15.06 (50-100) kg,respectively.

Results from this study can be found in Table 3 and Table 4.

TABLE 3 Mean pharmacokinetic (PK) parameters of levodopa followingsingle oral administration of Sinemet ® 25/100 orMadopar^( ®)/Restex^( ®) 125 on Day 2, Day 3 and Day 4. C_(max) t_(max)AUC₀₋₆ t_(1/2) Comparison Treatment (ng/mL) (h) (ng · h/mL) (h) Day 2Group 1 — 2513 0.5 4325 1.70 24 h before Group 2 — 2237 0.5 4294 1.63administration Group 3 — 2086 0.5 3830 1.88 of Compound A Group 4 — 18811.0 4141 1.78 Day 3 Group 1 Placebo 2103 0.5 3958 1.60 concomitant Group2 COMPOUND 2112 1.0 4545 1.97 administration A - 25 mg of Compound AGroup 3 COMPOUND 2366 0.5 4580 1.77 A- 50 mg Group 4 COMPOUND 2657 0.55440 2.05 A - 100 mg Day 4 Group 1 — 2128 0.5 3823 1.96 24 h after Group2 — 2369 0.5 4658 1.77 administration Group 3 — 2583 0.5 5178 1.84 ofCompound A Group 4 — 2479 1.0 5697 2.08

TABLE 4 Point estimates (PE) and 90% CI of mean PK parameters oflevodopa following single oral administration of Sinemet ® 25/100 orMadopar ®/Restex ® 125 and placebo, 25 mg, 50 mg and 100 mg COMPOUND Aon Day 3 and Day 4. C_(max) AUC₀₋₆ Comparison PE (90% CI) PE (90% CI)Day 3 (concomitant administration of compound A) Placebo - Day 3/Day 2 93.49 (62.23; 140.45)  82.11 (55.90; 120.61) COMPOUND A 25 mg - Day3/Day 2  90.10 (60.66; 133.84) 100.68 (66.58; 152.24) COMPOUND A 50 mg -Day 3/Day 2 117.00 (78.87; 173.56) 121.94 (88.57; 167.89) COMPOUND A 100mg - Day 3/Day 2  144.54 (104.41; 200.09)* 133.18 (90.22; 196.60) Day 4(24 h after administration of compound A) Placebo - Day 4/Day 2  83.26(55.84; 124.16)  93.45 (63.99; 136.48) COMPOUND A 25 mg - Day 4/ 109.18(80.03; 148.94) 110.54 (77.14; 158.40) Day 2 COMPOUND A 50 mg - Day 4/128.79 (87.27; 190.19)  138.79 (101.18; 190.38)* Day 2 COMPOUND A 100mg - Day 4/ 120.93 (79.59 183.74) 132.36 (86.56; 202.39) Day 2*significantly different.

Example 3d Clinical Trial in Patients with Parkinson's Disease: DosagePrior to Sleep

In this study, the Compound A is tested as the research therapy andentacapone and placebo as the reference therapies. Compound A isavailable in capsules of 5 mg, 25 mg and 50 mg. Entacapone tablets of200 mg are used. To ensure blinding during the Double Blind (DB) period,the Compound A capsules and entacapone tablets are identicallyover-encapsulated. The placebo capsules are prepared by fillingidentical capsules with filler (also used as back-filling). All placebocapsules contain, on average, 1 mg riboflavin to mimic the urinarydiscoloration seen as a harmless side effect of entacapone

Dosage Schedule

During the DB period, subjects take 1 capsule of treatment concomitantlywith each daytime levodopa/AADCi administration (3 to 8 dailyadministrations). An additional treatment (‘before bedtime’ or ‘prior tosleep’ administration) is administered at least 1 hour after the lastadministration of the day of levodopa/AADCi.

For the daytime administrations (i.e. taken concomitantly with eachlevodopa/AADCi administration), the treatment administration is asfollows:

-   -   Compound A Groups: placebo.    -   Entacapone Group: 200 mg entacapone.    -   Placebo Group: placebo.

For the bedtime dose (at least 1 hour after the last dailyadministration of levodopa/AADCi), the treatment administration is asfollows:

-   -   Compound A Groups: 5, 25 or 50 mg.    -   Entacapone Group: placebo.    -   Placebo Group: placebo.

Example 3e Clinical Trial in Patients with Parkinson's Disease: DosagePrior to Sleep and 1 Hour after Food Intake

In a double blind, placebo controlled study, patients with Parkinson'sdisease maintained on levodopa/AADCi are treated as follows. Patientstake either the placebo or compound A (25 mg or 50 mg) in the evening atleast one hour after the last dose of the day of levodopa/AADCi therapy(the bedtime dose (administration)).

Subjects are required to fast for 1 hour before and for at least 1 hourafter intake of the treatment.

Patients who take compound A are expected to show improved effectsrelative to those taking the placebo.

The invention claimed is:
 1. A method of treatment of Parkinson'sdisease, comprising administering to a human patient suffering from saiddisease a therapeutically effective amount of compound5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]3-nitrobenzene-1,2-diol or a pharmaceutically acceptablesalt, ester, carbamate or phosphate thereof, wherein the compound isadministered in combination with a catecholamine drug, wherein thecatecholamine drug is levodopa, and the compound is administered in asingle daily dose at least one hour before or after the last daily doseof the catecholamine drug.
 2. The method according to claim 1, whereinthe catecholamine drug is administered sequentially or concomitantlywith an aromatic L-amino acid decarboxylase inhibitor (AADCi).
 3. Themethod according to claim 2, wherein the AADCi is carbidopa orbenserazide.
 4. A method of treatment of Parkinson's disease, comprisingadministering to a human patient suffering from said disease atherapeutically effective amount of compound5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol,or a pharmaceutically acceptable salt thereof, wherein the compound isadministered in combination with a catecholamine drug, wherein thecatecholamine drug is levodopa, and the compound is administered in asingle daily dose at least one hour before or after the last daily doseof the catecholamine drug.
 5. The method according to claim 4, whereinthe catecholamine drug is administered sequentially or concomitantlywith an aromatic L-amino acid decarboxylase inhibitor (AADCi).
 6. Themethod according to claim 5, wherein the AADCi is carbidopa orbenserazide.